Ocular Allergy Ranges Ocular Allergy: an Updated from the Simplest Measures to the Most Complex Pharmacotherapy, Review Immunotherapy and Monoclonal Antibodies [6]

Journal of Allergy and Immunology

Review Article Open Access

will be discussed later. The management of ocular allergy ranges Ocular Allergy: an Updated from the simplest measures to the most complex pharmacotherapy, Review immunotherapy and monoclonal antibodies [6]. This manuscript highlights the classification of ocular allergy Buraa Kubaisi1,2, Khawla Abu Samra1,2, Sarah Syeda1,2, Alexander and provides details on the management options of ocular allergy Schmidt1,2* and Stephen C. Foster1-3 that include style modifications and the use of topical and systemic 1Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA medications. In addition the manuscript provides some insight on the use 2Ocular Immunology and Uveitis Foundation, Waltham, MA, USA of immunotherapy in the treatment of the most severe forms of ocular 3Harvard Medical School, Boston, MA, USA allergy and the recent advance in the use of monoclonal antibodies. *Corresponding author: Alexander Schmidt, Email: [email protected] Classification Received: 27 October 2016; Accepted: 13 January 2017; Published: 20 As mentioned earlier, the conjunctiva is the most common ocular January 2017 structure to be involved in ocular allergy, hence allergic conjunctivitis is used interchangeably. The traditional classification methods of allergic Abstract conjunctivitis stems from the cause of the ocular allergy, and can be described as seasonal and perennial allergic conjunctivitis, vernal Ocular allergy encompasses an inflammatory reaction of the keratoconjunctivitis, and atopic keratoconjunctivitis, and giant papillary surface of the eye that is caused by inappropriate response of the conjunctivitis. ocular surface to various environmental allergens. Since the majority of this inflammation involves the conjunctiva, the term “allergic Seasonal Allergic Conjunctivitis (SAC) and Perennial conjunctivitis” is often used interchangeably with ocular allergies. Allergic Conjunctivitis (PAC) Ocular allergy is a common problem that affects people of all ages in which the presentation may vary from being asymptomatic in SAC and PAC comprise most of the allergic conjunctivitis cases mild cases to serious and vision threatening inflammation in severe (about 95% in the United States) [7]. Although SAC and PAC are the cases. Subsets of ocular allergy include the predominantly ocular most common, the proportion of the more severe forms of ocular allergic itch-inducing seasonal allergic conjunctivitis (SAC), and perennial disease (AKC, VKC) increase in countries in the southern hemisphere allergic conjunctivitis (PAC) to more severe sight-threatening vernal [8]. Theories to explain this include increasing levels of industrialization keratoconjunctivitis (VKC), and atopic keratoconjunctivitis (AKC). and pollution or simply an anomaly arising from under-reporting of milder conditions [8]. The management of allergic conjunctivitis ranges from simple life style modifications and the regular use of pharmacologic therapy both SAC and PAC are distinguished from each other mainly by the topical and systemic, to more advanced therapy including allergen timing of exacerbations that could be related to different stimulating specific immunotherapy and a newly introduced anti-IgE antibody allergens in each [9]. SAC (commonly called hay fever conjunctivitis) novel therapy. is more common than PAC and worse during spring and summer times. The most frequent allergens responsible are mold spores or tree, weed, Keywords: Ocular allergy; Allergic conjunctivitis; Seasonal; or grass pollens, however the specific allergen varies with geographic Perennial; Vernal; Atopic location [4]. PAC causes symptoms throughout the year, generally Introduction worse in the autumn when exposure to house dust mites, animal dander, feathers and fungal allergens is greatest. It is less common and tends to Ocular allergy affects up to 40% of the population in the United be milder than the seasonal form [10,11]. The hallmark symptoms of States where allergic conjunctivitis considered the most common both SAC and PAC are itching and redness that are usually bilateral. cause of conjunctivitis Patients living with symptoms of ocular allergy Other symptoms include burning sensation and watering or sometimes endure a lower quality of life secondary to ailments that can range from mild mucoid discharge [10]. The conjunctivae are usually mildly ocular discomfort to vision loss [1,2]. Patientsmayalso suffer from the injected with various levels of chemosis [11]. Although the symptoms financial burden inflicted by the need for adequate management, which are usually bilateral, the degree of involvement may not be symmetric. can be life-long [2]. Furthermore, the global prevalence of ocular Cobblestoning is a sign generally not observed in the SAC or PAC allergies has steadily been on the rise, elevating the burden of this and indicates a more chronic and severe form of allergic conjunctivitis disease on the society [3]. although fine papillary hypertrophy of the upper tarsal conjunctiva Ocular allergy is often associated with nasal allergy symptoms, may occur [12,13]. The cornea is not usually involved in SAC or PAC [11,12]. hence the term ‘rhinoconjunctivitis’. Sixty four percent of patients with symptoms of allergic rhinitis report associated conjunctival symptoms Vernal Keratoconjunctivitis (VKC) of ocular allergy [4]. VKC is a more serious and potentially sight threatening form of A study of patients with hay fever found that ocular symptoms ocular allergy in which the stimulant (allergen) is usually not known alone were experienced in 8% of the study population, while 85.3 [14]. It is a chronic bilateral disease that typically affects young males % of the study population has a combination of both eye and nasal and usually resolves after puberty [14,15]. There is a history of eczema symptoms [5]. or asthma in 75 % of the patient [16]. VKC has a wide geographical Since the majority of the ocular allergic inflammation involves distribution, and usually occurs in warm, dry areas [17]. the conjunctiva, the term “allergic conjunctivitis” is often used KC can be classified to Palpebral, limbal and mixed forms. Palpebral interchangeably with ocular allergies [1,2]. Disorders that fall under form primarily involves the upper tarsal conjunctiva and may be the category of allergic conjunctivitis range from predominantly associated with significant corneal involvement as a result of the close ocular itch-inducing seasonal allergic conjunctivitis (SAC), and perennial allergic conjunctivitis (PAC) to more severe potentially sight-threatening Vernal keratoconjunctivitis (VKC), Atopic Copyright © 2017 The Authors. Published by Scientific Open Access Journals LLC. keratoconjunctivitis (AKC), as well as some other disorder that Kubaisi et al. Volume 1, Issue 1 J Allergy Immunol 2017; 1:002 apposition between the inflamed conjunctiva and the corneal epithelium the above mentioned ocular syndromes and considered part of the [16,18]. Limbal form typically affects black and Asian patients and differential diagnosis include both contact blepharo-conjunctivitis and is usually limited to the perilimbal area. Mixed VKC basically has phlyctanular keratoconjunctivitis features of both palpebral and limbal disease [16,18]. Patients usually have a year-round disease but seasonal flare-ups are common. The Contact Blepharo-Conjunctivitis main symptom of VKC is itching. Other common symptoms include This refers to the acute or subacute reaction that is seen most tearing, mucus discharge, photophobia, pain, burning and foreign body commonly as a reaction to eye drop constituents or sometimes as a sensation [16,18] The signs are mostly confined to the conjunctiva reaction to contact lens solutions [24]. It usually happens in the early and cornea, while the eyelid skin is relatively uninvolved [18] The course of treatment but can be seen after chronic use of the same drop. hallmark finding of VKC is the cobblestone-like giant papillae of the The signs predominantly involve the eyelid skin (erythema, thickening, upper tarsal conjunctiva [16,18,19]. induration), although there may be a conjunctival reaction [24]. It Bulbar conjunctiva is usually edematous and injected. The peri- appears that the preservative may be largely responsible for allergic, limbal conjunctiva may be thickened and edematous forming a toxic or inflammatory reactions, although antiglaucoma and antibiotic gelatinous-like hypertrophy [18] Limbal nodules and Trantas dots drops are not uncommon causes [24]. composed of eosinophils and dead epithelial cells may be observed Phlyctenular Keratoconjunctivitis (PKC) [16]. These limbal changes may sometimes lead to superficial neovascularization of the cornea and pannus. The most important and PKC is a nodular inflammation of the conjunctiva or cornea vision threatening complications occur in the cornea as mild epithelial that results from a hypersensitivity reaction to a foreign antigen. keratitis or in more severe cases as shield ulcers. [16,18] A shield ulcer Conjunctival involvement is usually transient and asymptomatic, but results from chemical damage to the epithelial surface by mediators corneal involvement can occur in various forms and can lead to visual released from mast cells and eosinophils. Shield ulcers are typically impairment. In the past, tuberculin protein was thought to be the main oval or pentagonal, superficial, and superiorly located with grayish antigen responsible for PKC, however, with improvement of public opacification of the bed and elevated margins [18]. They may take health, microbial proteins of staphylococcus aureus were found to be the months to re-epithelize and in chronic advanced cases they may form most common causative antigens in PKC. Risk factors for staphylococcus an opaque white or yellow plaque [18]. It is also known that there is a aureus exposure include chronic blepharitis and suppurative keratitis. strong association between VKC and keratoconus [18]. PKC is more common in females and has a higher incidence during Atopic Keratoconjunctivis (AKC) spring [25]. The clinical presentation of PKC varies depending on its location as well as the underlying etiology. Conjunctival lesions AKC was first described by Michael Hogan in 1952 as an allergic may cause only mild to moderate irritation of the eye, while corneal keratoconjunctivitis occurring in association with allergic dermatitis lesions typically may have more severe pain and photophobia. More [20]. AKC occurs in both children and adults and is associated with severe light sensitivity may occur with tuberculosis related phlyctenules eczema of the lids or of other parts of the body [20]. AKC most compared to S. aureus related phlyctenules [26]. PKC presents as a frequently occurs in men and typically starts in the late teens or early nodular lesion with injection of the surrounding conjunctival vessels twenties but rarely before puberty, and may persist until the fourth and may show some ulceration and staining with fluorescein as they or fifth decade of life. The main ocular symptoms include extreme progress. Conjunctival phlyctenules occurs more commonly in the itching, photophobia, burning and foreign body sensation [20,21]. interpalpebral conjunctiva and are frequently noted along the limbal The patients usually wake up with copious mucous discharge gluing region. Sometimes, multiple nodules may be found along the limbal the eyes together. Eyelid disorders are the most common ocular surface. Corneal phlyctenules usually starts at the limbal region and complications of atopic dermatitis and they are often red, macerated frequently progress to corneal ulceration and neovascularization that with crusting and scaling, which are not symptoms seen in patients can lead to scarring and various degrees of vision loss. The diagnosis with VKC [21]. In severe cases of AKC conjunctival scarring with sub of PKC is made based on the history and clinical examination findings. epithelial fibrosis, fornix foreshortening and symblepharon may occur When thinking about an infectious etiology, further investigations [21]. Corneal ulceration and neovascularization may also occur. The to rule out tuberculosis or chlamydia should be done and if positive, conjunctival scarring of AKC may be confused with other cicatrizing appropriate systemic treatment is required. diseases like ocular cicatrizing pemphigoid [21]. Pathophysiology Giant Papillary Conjunctivitis (GPC) SAC and PAC are classic Gell and Coombs type 1 hypersensitivity GPC is usually seen in patients with contact lenses, but also can be reactions, occurring as a consequence of inappropriate (atopic or “out of seen in patients with corneal foreign bodies, exposed sutures, ocular place) immune responses to ordinarily harmless materials which elicit prosthesis and extruded scleral buckle [22]. GPC is described as an immune response in those individuals who are genetically destined papillae on the upper tarsal conjunctiva with a size of 1 mm or larger in to make such responses as a consequence of inadequate regulation, with diameter [22]. Also papules with a size of 0.3 mm or larger associated IgE antibody production directed against the allergens and subsequent with the symptoms of itching, contact lens intolerance or conjunctival binding of those IgE molecules to Fc receptors on the surface of injection, meet the criteria for the diagnosis of GPC [23]. mucosal mast cells. Subsequent contact with the sensitizing allergen results in binding of allergen to those IgE molecules, and when such Patients with GPC has symptoms of contact lens intolerance, binding to two adjacent IgE molecules occurs, a change in membrane blurry vision, excessive mucous secretion, itching and ocular irritation adenyl cyclase occurs, changing the intracellular concentration of cyclic [22,23]. It is important to mention that large papillae in the medial AMP, resulting in opening of calcium gates, with a spike in intracellular and lateral aspects of the upper tarsus and the ones along the tarsal calcium concentrations. This, then results in the aggregation of tubulin border should not be used in evaluation as they may be seen in normal subunits, forming microtubules, resulting in degranulation and a individuals. It is to be mentioned that the hypertrophied papillae in the release of preformed histamine and proteases, triggering a type I tarsal conjunctiva can sometimes lead to ptosis [22,23]. hypersensitivity response [27,28]. This causes itching, tearing, edema Other Ocular Allergy Disorders and redness which lasts 20-30 minutes. Mast cells continue to produce late-phase reactants such as prostaglandins, leukotrienes, platelet- Other ocular surface allergy disorders that may be confused with activating-factor and chemotactic cytokines that result in recruitment of

Citation: Kubaisi B, Samra KA, Syeda S, et al. Ocular Allergy: an Updated Review. J Allergy Immunol 2017; 1:002. Kubaisi et al. Volume 1, Issue 1 J Allergy Immunol 2017; 1:002 other inflammatory cells, producing a sustained inflammatory reaction Topical medications include antihistamine/vasoconstrictor characterized by neutrophil and eosinophil activation and increased combination products, antihistamines with mast cell stabilizing vascular permeability and microvascular dilation [29], the so-called properties, mast cell stabilizers, and, topical glucocorticoids late phase reaction, which is subclinical in SAC and in PAC, but manifest in the more complex and vision threatening ocular allergies. Topical Vasoconstrictors (decongestants) and Antihistamines While the pathogenesis of VKC and AKC also involves -mediated chronic mast cell degranulation, the inflammation is primarily Th2 Topical decongestants were the first agents to be approved for the lymphocyte-mediated [30], involving a much more complex cast treatment of allergic conjunctivitis. Tetrahydrozoline was marketed in of cellular characters than that of SAC and PAC. In VKC, Th2 the 1950s and naphazoline in 1971. While decongestants are effective lymphocyte-derived cytokines result in an over-expression of mast for ocular hyperemia, they have no effect on itching and are subject cells, eosinophils, neutrophils and conjunctival fibroblasts, and the to tachyphylaxis [35]. Ocular decongestants were paired early on with added storm of growth factors, IL-4 and IL-13 results in the growth topical antihistamines such as pheniramine and antazoline to combat of the extracellular matrix, culminating in the formation of giant both the itching and redness associated with allergic conjunctivitis papillae [31]. And the cytokine recruitment of eosinophils to the [25,37]. These topical medications are appropriate for short-term or episodic use only. Regular use for longer than two weeks can lead to affected area is especially devastating, with the liberation of eosinophil rebound hyperemia because of the vasoconstrictor component [37]. major basic protein and eosinophil cationic protein, both of which are highly toxic to corneal epithelium. Thus, VKC and AKC and even The antihistamine component competitively and reversibly GPC are complex combined Type 1 and Type 4 Gell and Coombs blocks histamine receptors in the conjunctiva and eyelids, thus hypersensitivity reactions. The pathogenesis of AKC is similar, inhibiting the actions of the primary mast cell-derived mediator. but is also thought to include Th1 lymphocyte-derived cytokines The vasoconstrictor component activates the post-junctional, alpha- [32]. In contrast to the above, contact allergy is classified as a type adrenergic receptors found in blood vessels, causing vasoconstriction IV hypersensitivity reaction [33]. During sensitization, allergens, and decreased conjunctival edema. Examples of topical antihistamine/ which are simple chemicals that combine with skin proteins to form vasoconstrictor drugs include naphazoline and pheniramine (available antigens, are processed by MHC class II on T lymphocytes to induce as Naphcon-A, Opcon-A, Visine-A, and others). Dosing is up to four production of memory T cells [34]. Subsequent exposure results to times daily during acute symptoms. Single agent topical products memory T cells and the production of cytokines and proliferation (vasoconstrictors or antihistamines only) are also available without a of T cells. Cytokines released from Th1 cells and Th2 cells mediate prescription, although the combination products usually work better the recruitment of macrophages and eosinophils, respectively, which [37,38]. result in the pathogenesis of conjunctivitis. In the 1990s the most efficacious and commercially successful Management of Ocular Allergy second generation antihistamine became available in the market and included the topical ophthalmic eye drops levocabastine and emedastine The management of ocular allergy in general involves preventive [37]. Levocabastine and emedastine were indicated for the temporary measures, non-pharmacologic as well as pharmacologic measures. relief of the signs and symptoms of seasonal allergic conjunctivitis and Preventive measures include identification of provocative allergens allergic conjunctivitis respectively. Levocabastine is the first topical and avoidance or reduction, as much as possible, of contact with known antihistamine with multiple mechanisms that impacted both the early allergens and appropriate management of environmental exposure and late-phases of ocular allergic reactions through the upregulation of [35]. This is a measure at which allergists are most adept. In addition, eosinophil activation and infiltration [39]. prevention of symptoms of seasonal allergic conjunctivitis includes Mast-cell Stabilizers limiting outdoor exposure, and keeping car and home windows closed during the peak pollen seasons [35,36]. For patients with perennial Cromolyn sodium (also known as sodium cromoglycate) was allergic conjunctivitis, prevention includes avoidance of the specific approved in 1984 for the treatment of vernal keratoconjunctivitis. allergens that are causing symptoms in a specific patient. For those Lodoxamide has an identical indication and was approved in 1993. allergic to dust mites, helpful measures include replacing old pillows, Lodoxamide has a greater potency and rapidity of action than cromolyn blankets, and mattresses. Measures also include using dust mite sodium; in addition it also appears to be more efficacious against the allergen impermeable covers for pillows, comforters, and mattresses. Table 1: Details of different types of ocular allergy. Additionally, other reservoirs of dust should be removed, such as old carpets, old furniture, and old curtains or drapes. If the patient is Signs and SAC/PAC VKC ACK GPC allergic to animal dander, the animal may need to be removed from the symptoms home, and old carpets, furniture, and curtains should be removed or White Discharge clear/mucoid mucoid mucoid clear cleaned thoroughly [35,36]. Air cleaners with frequent replacement of Itchy + ++ ++ ++ the filters are very useful. Chemosis + +/- +/- +/- Corneal The non-pharmacologic measures include avoiding eye rubbing - ++ + - as this result in mechanical mast cell degranulation and worsening of involvement symptoms. This may have become a habit and thus may be very difficult Cobblestoning - ++ ++ ++ to change. In addition the use of cool compresses and refrigerated Lid involvement - +/- ++ +/- artificial tears throughout the day has been found to be effective in Seasonal + + +/- +/- reducing eyelid and periorbital edema and removing allergens from the variation eye as showed by Bilkhu et al. [36]. The use of contact lens should be Systemic eczema/ rhinitis - - limited during the acute stage of the allergic conjunctivitis. association asthma Pharmacologic Therapy + present; - absent; +/- present or absent; ++ pronounced. SAC, Seasonal allergic conjunctivitis; PAC, Perennial allergic conjunctivitis; This includes both topical and systemic medications for acute and AKC, atopic keratoconjunctivitis; VKC, vernal keratoconjunctivitis; chronic management GPC, Giant papillary conjunctivitis.

Citation: Kubaisi B, Samra KA, Syeda S, et al. Ocular Allergy: an Updated Review. J Allergy Immunol 2017; 1:002. Kubaisi et al. Volume 1, Issue 1 J Allergy Immunol 2017; 1:002 epithelial damage and shield ulcers related to vernal keratoconjunctivitis shown to reduce both provocation-induced early phase itching, and [40]. Nedocromil sodium, was approved in 1999 for ocular itching the late-phase ocular itching and hyperemia associated with seasonal associated with allergic conjunctivitis and has shown a greater efficacy allergic conjunctivitis [29]. than cromolyn sodium [41] The full efficacy of mast cell stabilizers is normally reached 5 to 14 days after therapy has been initiated and Topical Immune-Modulators therefore these eye drops are not effective for acute symptoms [42]. Both cyclosporine A, and tacrolimus have been evaluated Mast cell stabilizers are administered four times daily and patients previously for the management of vision-threatening and severe with seasonal allergic conjunctivitis should begin treatment two to four vernal keratoconjunctivitis and atopic keratoconjunctivitis [50,51]. weeks before the pollen season [40-42]. In a large prospective observational study, 594 patients with vernal Antihistamines with Mast Cell-stabilizing keratoconjunctivitis and atopic keratoconjunctivitis were included to evaluate the efficacy of topical cyclosporine. The study showed that the Properties use of topical cyclosporine A 0.1% significantly decreased all objective This group of eye drops includes olopatadine, alcaftadine, and subjective scores, including itching. In addition 44.4% of patients bepotastine, azelastine HCl, epinastine, ketotifen fumarate, and with VKC and 21.9% of patients with AKC stopped therapy due to emedastine. In the United States, Ketotifen fumarate is available complete resolution of symptoms, and approximately 30% of steroid in a generic form and can be purchased over the counter with no users were able to discontinue concomitant topical steroid use. Eye prescription. The usual dose is twice per day for most products. There irritation was the most common adverse event (4.4%) and all infectious are three antihistamine/mast cell stabilizing drops approved for once incidents (n = 10) occurred in subjects undergoing concomitant steroid daily dosing – alcaftadine 0.25%, olopatadine 0.2%, and olopatadine use [52]. 0.7%; only alcaftadine is pregnancy category B [43]. Onset of action is Topical tacrolimus, used either as 0.03% ointment or 0.1% within minutes for most drugs. At least two weeks of therapy should be ophthalmic suspension, also appears safe and effective, and the 0.1% allowed in order to assess the full efficacy of prophylactic therapy with ophthalmic suspension may be more effective at resolving giant papillae these agents, since it may take some time for the inflammation to be because of VKC and AKC. Compared to cyclosporine, Tacrolimus is controlled and symptoms to subside completely. Side effects of these 100-fold more potent. It blocks cellular steroid receptors, inhibiting eye drops may include stinging and burning sensation. Refrigerating mediator release from mast cells and, thereby, suppressing T-cell the drops and/or use refrigerated artificial tears prior to using these activation and consequent B-cell proliferation [51] Topical tacrolimus medications are effective ways to decrease burning sensation [42]. 0.3%, compared to the 0.1% and 0.005% formulation, apparently offers A randomized study that compared cromolyn sodium use (4 percent, the optimal efficacy in treatment of ocular itching and improvement four times daily) for two weeks prior to allergen challenge with a across all other subjective and objective measures [53]. single drop of ketotifen fumarate (0.025 percent) given just before allergen challenge found that the single drop of ketotifen was superior Systemic Therapy in controlling itching and redness at 15 minutes and at 4 hours after challenge [44]. Oral antihistamines Nonsteroidal Anti-inflammatory Drugs In cases of seasonal allergies, systemic over-the-counter, or prescription antihistamines may be helpful for symptoms of rhinitis Specific prostaglandins are thought to lower the conjunctival and generalized pruritus. In cases of ocular symptoms, randomized threshold for histamine-induced itching, and the prostaglandins trials have shown that topical antihistamines are more effective than may be pruritogenic themselves as well. Topical nonsteroidal anti- oral medications for ocular symptoms. Specifically, topical olopatadine inflammatory drugs (NSAIDs) inhibit prostaglandin and leukotriene was more effective than oral olopatadine or fexofenadine, and topical production, thus helpful in allergic conjunctivitis [45]. ketotifen was more effective than oral desloratadine [54,55]. In NSAIDs commonly prescribed for ocular allergy include addition, oral antihistamines can cause drying of mucosal membranes ketorolac, diclofenac, indomethacin, and flurbiprofen. However, and decreased tear production in some patients, especially those with only ketorolac is indicated for the temporary relief of ocular itching concomitant dry eye [56]. due to seasonal allergic conjunctivitis [46]. Although Ketorolac Some oral antihistamines have shown efficacy in the treatment of is the only NSAID approved for the treatment of seasonal allergic allergic conjunctivitis, compared with placebo, in different clinical conjunctivitis, topical formulations of indomethacin, ketorolac, and studies [57,58]. Oral administration of antihistamines results in peak diclofenac have demonstrated efficacy in the treatment of vernal serum levels in 30 minutes to 3 hours, depending on the specific drug. keratoconjunctivitis [46]. Full effects are seen after several days of use. Thus, these agents have Glucocorticoids a slower onset of action compared with topical agents, unless they are taken prophylactically. Topical corticosteroid administration should be limited for use in patients with refractory symptoms such as symptoms associated Systemic immunomodulators with vernal keratoconjunctivitis and atopic keratoconjunctivitis. Patients with refractory severe disease or vision-threatening allergy Topical corticosteroids are not effective in the early phase allergic may benefit from systemic immunosuppressive therapy. Guidelines reaction; however by inhibiting the production and/or release of the regarding systemic immunosuppressive therapy are not available in the inflammatory mediators they are very effective in suppressing the late- literature except for isolated case reports [59,60]. phase reaction [47,48]. The long-term use of topical corticosteroids is associated with potentially serious and sight-threatening side effects This group of medications include the calcineurin and mTOR themselves such as increased intraocular pressure (IOP) and risk of inhibitors Cyclosporine A , Tacrolimus and pimecrolimus. These cataract formation [47]. Loteprednol, has been approved in 1998 for medications have not been approved in Europe or the United States the treatment of allergic conjunctivitis. It belongs to the new class of for the treatment of ocular allergy (approved only in Japan), and their corticosteroids that reduce the risk of increased IOP by being rapidly use should be reserved to selected patients who are followed in referral converted into inactive metabolites following corneal penetration centers. Cyclosporine A is effective in controlling ocular inflammation [49]. Although the corticosteroid Difluprednate is mainly indicated for by blocking Th2 lymphocyte proliferation and interleukin 2 (IL) the management of postoperative inflammation and pain, it has been productions. It also inhibits histamine release from mast cells and

Citation: Kubaisi B, Samra KA, Syeda S, et al. Ocular Allergy: an Updated Review. J Allergy Immunol 2017; 1:002. Kubaisi et al. Volume 1, Issue 1 J Allergy Immunol 2017; 1:002 basophils and, through a reduction of IL-5 production; it may reduce (FDA) in the past, reports of adverse effects are lacking and most the recruitment and the effects of eosinophils on the conjunctiva [59]. ophthalmologists are comfortable with their safety [72]. In a previous study it has been demonstrated that in severe cases Topical glucocorticoids should be used with caution in pregnant of ocular allergy, resistant to conventional therapy, systemic treatment women and under the supervision of both an ophthalmologist and an with T-lymphocyte signal transduction inhibitors may ameliorate obstetrician. Allergen immunotherapy is another option for severe both the dermatologic and ocular manifestations [60]. In this study, symptoms and Immunotherapy is not initiated during pregnancy. systemic cyclosporine A, dosed 2.5 mg/kg/day in divided doses, has Vasoconstrictor and decongestant eye drops are generally avoided been successfully used for the treatment of severe AKC and dry-eye during pregnancy [73]. disease. However, potential toxicity restrict long term use of these products [60]. Allergic periocular dermatitis In another study, 4 patients (aged 31-64) with severe atopic If a contact allergy has been established as the cause of periocular keratoconjunctivitis and atopic dermatitis refractory to or dependent on dermatitis, the treatment of choice is to avoid the allergen. steroid therapy were treated with Cyclosporine 3 to 5 mg/kg and mean In cases of atopic dermatitis, treatment is typically multimodal, duration treatment 37 months. Ocular inflammation was controlled involving topical therapies, emollients, treatment of infection if present, totally in three patients and partially in one patient [61]. In a 6 year old use of oral antihistamines for pruritus, and avoidance of triggering child with severe and vision threatening vernal keratoconjunctivitis, a factors. Symptoms of atopic dermatitis involving the periocular tissues dramatic improvement and stabilization of his symptoms was achieved may be treated with calcineurin inhibitors [74]. with oral cyclosporine therapy [62]. In December 2000 topical tacrolimus ointment 0.03% was approved Allergen-specific immunotherapy by the FDA for clinical use in moderate to severe AD for ages 2 years Immunotherapy as a treatment for allergic diseases, was first and up, with the higher strength 0.1% approved for ages 16 years and up. introduced by Noon and Freeman in 1911 as a means of treating hay A year later, pimecrolimus was approved for mild and moderate atopic fever (rhinoconjunctivitis) [63]. In this therapy, patient with allergies dermatitis for ages 2 years and up. Numerous studies have demonstrated receives increasing doses of an allergen-containing extract, comprised their efficacy in atopic dermatitis [74]. Evidence-based confirmation of of the relevant allergens to which the patient is sensitive, in an attempt the safety of topical calcineurin inhibitors in the treatment of atopic to suppress or eliminate allergic symptomatology [63]. Allergen- dermatitis involving the face has been established in the literature [75]. specific immunotherapy is typically recommended for patients whose Although the only approved indication for calcineurin inhibitors is allergic rhinoconjunctivitis and asthma symptoms cannot be controlled treatment of atopic dermatitis, a number of placebo-controlled and open by medication and environmental control, who cannot tolerate their studies have shown the effectiveness of topical calcineurin inhibitors medications, or who do not comply with chronic medication regimens. in the treatment of periorbital contact dermatitis, irritant contact With continuous administration of allergens it is expected that the dermatitis, seborrheic dermatitis, rosacea, facial, and intertriginous treatment regimen will make the patient tolerant to the offending psoriasis vulgaris [76-78]. allergen and suppress future untoward responses to the allergen(s) through modulation of the patient’s immune system [64,65]. Future Perspective Allergen specific immunotherapy is believed to be the only therapeutic With increasing knowledge and advance in medicine engineering option capable of changing the natural course of allergic disease and technology, the future of many disorders including ocular allergy has demonstrated long-term, disease-modifying effects [66]. is expected to change in a better direction. Given the pivotal role of Allergen specific immunotherapy may be administered by either IgE in the allergic cascade, antibodies directed against IgE or other the subcutaneous or sublingual route. It has been shown that both allergic mediators represent the future therapeutic approach to allergic methods are effective at treating allergic conjunctivitis [67]. However, conjunctivitis. A relatively new and promising drug that is being in patients with polysensitization, the injection method shows superior introduced into the ocular allergy clinical practice with encouraging results [68]. results include the recombinant humanized monoclonal antibody Omalizumab. Studies showed that symptoms of rhinoconunctivitis had improved following the use of sublingual immunotherapy with symptom/ Omalizumab, an anti IgE antibody, is successfully used for the medication score improvements of up to 27–28% for ragweed and treatment of IgE mediated allergic disorders including persistent atopic asthma, atopic dermatitis, urticaria, eosinophil-associated grass pollen [69,70]. It has been recently suggested that dust mite sublingual immunotherapy may also be effective for allergic rhinitis gastrointestinal diseases and seasonal rhinoconjunctivitis [79,80]. with or without conjunctivitis. In a randomized, double-blind placebo- Despite the lack of randomized clinical trials studying this drug in controlled study, authors demonstrated reduced nasal and ocular ocular allergy, few case reports showed omalizumab to be an effective symptoms in adults treated with a dust mite sublingual immunotherapy and promising drug in the in the treatment of severe ocular allergy tablet undergoing allergen challenge in an exposure chamber [71]. [79,81]. The lack of evidence based medicine on the use of these drugs in cases of ocular allergy, make it very difficult to agree on guidelines Special Situations and recommendations for using these drugs. Clinical trial evaluating the Ocular allergy in pregnancy efficacy and safety are required. The first step should include non-pharmacologic measures and Conclusion allergen avoidance. If such measures do not control symptoms Ocular allergy is a very common ocular inflammatory disorder with adequately, cromolyn sodium eye drops may be tried next. If allergen a significant impact on the quality of patient’s life. Better understanding exposure is predictable (eg, pollen season), therapy should be initiated of the allergic mechanisms, inflammation, and classification helps two weeks before [72]. physicians plan for and achieve the best treatment, thus the best control If cromolyn sodium eye drops are not enough to control the of symptoms. Some forms of ocular allergy can be controlled following symptoms, antihistamine eye drops may be used. Although these agents simple life style modifications and traditional treatment delivered by were assigned a category C by the US Food and Drug Administration a general ophthalmologist. However, some other forms of ocular

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Citation: Kubaisi B, Samra KA, Syeda S, et al. Ocular Allergy: an Updated Review. J Allergy Immunol 2017; 1:002.